More than 30% adult population report inadequate sleep. Sleep loss is a major public health problem and is estimated to cost our society nearly 56 billion dollars each year. Effects of inadequate sleep on poor job performance are well recognized, but effects on disease susceptibility are not clear. Conventional wisdom holds that sleep is good therapy for disease prevention. By inference, sleep loss should promote disease and compromise immune function. However, recent findings show that sleep loss activates indicators of innate immunity with increased monocytes and natural killer (NK) cells, increased NK cytotoxicity, and enhanced tumor regression. This increased immune activity may reflect a response to microbial translocation, which is also associated with sleep loss. Sleep loss leads to activation of neuroendocrine and sympathetic systems that down regulate immune activity. We hypothesize that sleep loss-induced altered response to NK cell specific tumor challenge depends upon a balance between stimulation of an immune response by microbes and depression of the response by neuroendocrine and sympathetic activity. We propose to study effects of 72 h sleep loss and 48 h recovery from sleep loss on indicators of innate immunity (numbers of monocytes and NK cells, NK cytotoxicity, and cytokine release from cultured cells) in peripheral blood and spleen, microbial translocation (incidence of bacteria in lymph nodes), neuroendocrine and sympathetic activity (ACTH, corticosterone in plasma; norepinephrine in spleen), and in vivo NK-sensitive tumor challenge. A standard method of sleep loss will be used in a series of controlled experiments. Numbers of NK cells and monocytes will be distinguished by flow cytometry. Cytokines secreted by NK cells and monocytes (Tumor necrosis factor-alpha, Interferon-1-beta) will be quantified by ELISA. Bacteria will be quantified by standard microbiological techniques. Hormones will be measured by HPLC or RIA assays. Clearance of injected radiolabeled MADB106NK sensitive tumor cells from lung will be quantified. The proposed series of studies will compare differences in outcomes after sleep loss and after recovery from sleep loss. We will examine relationships among indicators of microbial translocation, neuroendocrine, sympathetic and immune activity. When more is known about effects of sleep loss on immune function, interventions then can be devised to alleviate or compensate for altered disease outcomes.